Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice

Previous studies on the effect of glycosylation on the elimination rate of antibodies have produced conflicting results. Here, we performed pharmacokinetic studies in mice with two preparations of a monoclonal IgG1 antibody enriched for complex type or high mannose type oligosaccharides at the Fc glycosylation site. No significant difference in the serum half-life was found between the two antibody glycoforms, nor was any difference observed in the serum half-lives of different complex type glycoforms. To evaluate the influence of glycosylation within the variable domain, a second monoclonal antibody, glycosylated in both the Fc and Fv domains, was separated into fractions containing different amounts of Fv-associated sialic acid and administered to mice. Again, no significant difference was found in the clearance rates of variants carrying different amounts of Fv-associated sialic acid or lacking Fv-glycosylation. These results suggest that glycosylation has little or no impact on the pharmacokinetic behavior of these two monoclonal antibodies in mice.

Hip damage occurs at the zone of femoroacetabular impingement

Although current concepts of anterior femoroacetabular impingement predict damage in the labrum and the cartilage, the actual joint damage has not been verified by computer simulation. We retrospectively compared the intraoperative locations of labral and cartilage damage of 40 hips during surgical dislocation for cam or pincer type femoroacetabular impingement (Group I) with the locations of femoroacetabular impingement in 15 additional hips using computer simulation (Group II). We found no difference between the mean locations of the chondrolabral damage of Group I and the computed impingement zone of Group II. The standard deviation was larger for measures of articular damage from Group I in comparison to the computed values of Group II. The most severe hip damage occurred at the zone of highest probability of femoroacetabular impact, typically in the anterosuperior quadrant of the acetabulum for both cam and pincer type femoroacetabular impingements. However, the extent of joint damage along the acetabular rim was larger intraoperatively than that observed on the images of the 3-D joint simulations. We concluded femoroacetabular impingement mechanism contributes to early osteoarthritis including labral lesions. LEVEL OF EVIDENCE: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Femoroacetabular impingement: radiographic diagnosis- what the radiologist should know

OBJECTIVE: The purpose of this article is to show the important radiographic criteria that indicate the two types of femoroacetabular impingement: pincer and cam impingement. In addition, potential pitfalls in pelvic imaging concerning femoroacetabular impingement are shown. CONCLUSION: Femoroacetabular impingement is a major cause for early "primary" osteoarthritis of the hip. It can easily be recognized on conventional radiographs of the pelvis and the proximal femur.

Becoming most fully ourselves : gender, voice, and ritual in dissertations

The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher. Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse.

Antiaggregatory and proangiogenic effects of a novel recombinant human dual specificity anti-integrin antibody

BACKGROUND: beta(3)-Integrins are involved in platelet aggregation via alpha(IIb)beta(3) [glycoprotein (GP)IIb-GPIIIa], and in angiogenesis via endothelial alpha(V)beta(3). Cross-reactive ligands with antiaggregatory and proangiogenic effects, both desirable in peripheral vasculopathies, have not yet been described. OBJECTIVES: In vitro and in vivo characterization of antiaggregatory and proangiogenic effects of two recombinant human Fab fragments, with emphasis on beta(3)-integrins. METHODS: Recombinant Fab fragments were obtained by phage display technology. Specificity, affinity and IC(50) were determined by immunodot assays, enzyme-linked immunosorbent assay (ELISA), and Scatchard plot analysis, and by means of human umbilical vein endothelial cells (HUVECs). Functional analyses included ELISA for interaction with fibrinogen binding to GPIIb-GPIIIa, flow cytometry for measurement of activation parameters and competitive inhibition experiments, human platelet aggregometry, and proliferation, tube formation and the chorioallantoic membrane (CAM) assay for measurement of angiogenic effects. RESULTS: We observed specific and high-affinity binding to an intact GPIIb-GPIIIa receptor complex of two human Fab autoantibody fragments, with no platelet activation. Dose-dependent fibrinogen binding to GPIIb-GPIIIa and platelet aggregation were completely inhibited. One Fab fragment was competitively inhibited by abciximab and its murine analog monoclonal antibody (mAb) 7E3, whereas the other Fab fragment bound to cultured HUVECs, suggesting cross-reactivity with alpha(V)beta(3), and also demonstrated proangiogenic effects in tube formation and CAM assays. CONCLUSIONS: These Fab fragments are the first entirely human anti-GPIIb-GPIIIa Fab fragments with full antiaggregatory properties; furthermore, they do not activate platelets. The unique dual-specificity anti-beta(3)-integrin Fab fragment may represent a new tool for the study and management of peripheral arterial vasculopathies.

Impingement-free hip motion: the 'normal' angle alpha after osteochondroplasty

Femoroacetabular impingement is considered a cause of hip osteoarthrosis. In cam impingement, an aspherical head-neck junction is squeezed into the joint and causes acetabular cartilage damage. The anterior offset angle alpha, observed on a lateral crosstable radiograph, reflects the location where the femoral head becomes aspheric. Previous studies reported a mean angle alpha of 42 degrees in asymptomatic patients. Currently, it is believed an angle alpha of 50 degrees to 55 degrees is normal. The aim of this study was to identify that angle alpha which allows impingement-free motion. In 45 patients who underwent surgical treatment for femoroacetabular impingement, we measured the angle alpha preoperatively, immediately postoperatively, and 1 year postoperatively. All hips underwent femoral correction and, if necessary, acetabular correction. The correction was considered sufficient when, in 90 degrees hip flexion, an internal rotation of 20 degrees to 25 degrees was possible. The angle alpha was corrected from a preoperative mean of 66 degrees (range, 45 degrees - 79 degrees) to 43 degrees (range, 34 degrees - 60 degrees) postoperatively. Because the acetabulum is corrected to normal first, the femoral correction is tested against a normal acetabulum. We therefore concluded an angle alpha of 43 degrees achieved surgically and with impingement-free motion, represents the normal angle alpha, an angle lower than that currently considered sufficient.

[Complementary and alternative medicine in primary care in Switzerland]

OBJECTIVE: This study investigated the current supply of complementary and alternative medicine (CAM) in Swiss primary care. Information was collected on physicians' qualifications in CAM, frequency of patients' demand for CAM, physicians' supply and temporal resources for CAM as well as physicians' referrals to CAM. MATERIAL AND METHODS: 750 (500 German-speaking and 250 French-speaking) randomly selected Swiss female and male primary care physicians were asked to complete a questionnaire (response rate 50.4%). Sociodemographic data on professional training, place of residence, and sex were used to calculate a weighting factor to correct the responders' data in the analysis accordingly. RESULTS: 14.2% of the physicians were qualified in at least one CAM discipline. Around 30% (95% confidence interval 25.4-34.6%) of the physicians were asked for CAM by their patients more than once a week. Homeopathy and phytotherapy were the most frequently offered therapies, followed by traditional Chinese medicine (TCM)/acupuncture. 62.5% (57.6-67.4%) of the physicians refer their patients to CAM. Most patients were referred to TCM/acupuncture. Of the 37.2% (32.6-42.4%) of the physicians who do not refer their patients to CAM, around 40% (35.1-44.9%) offer it themselves. CONCLUSION: About three quarters of the physicians offer CAM themselves or refer their patients to CAM treatments. CAM is very important in primary medical care in Switzerland. Clear regulations for CAM are required in order to ensure a high quality in care.

Cartilage damage in femoroacetabular impingement (FAI): preliminary results on comparison of standard diagnostic vs delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC)

OBJECTIVES: To study the three-dimensional (3D) T1 patterns in different types of femoroacetabular impingement (FAI) by utilizing delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) and subsequent 3D T1 mapping. We used standard grading of OA by Tonnis grade on standard radiographs and morphological grading of cartilage in MRI for comparative analysis. METHODS: dGEMRIC was obtained from ten asymptomatic young-adult volunteers and 26 symptomatic FAI patients. MRI included the routine hip protocol and a dual-flip angle (FA) 3D gradient echo (GRE) sequence utilizing inline T1 measurement. Cartilage was morphologically classified from the radial images based on the extent of degeneration as: no degeneration, degeneration zone measuring <0.75 cm from the rim, >0.75 cm, or total loss. T1 findings were evaluated and correlated. RESULTS: All FAI types revealed remarkably lower T1 mean values in comparison to asymptomatic volunteers in all regions of interest. Distribution of the T1 dGEMRIC values was in accordance with the specific FAI damage pattern. In cam-types (n=6) there was a significant drop (P<0.05) of T1 in the anterior to superior location. In pincer-types (n=7), there was a generalized circumferential decrease noted. High inter-observer (intra-observer) reliability was noted for T1 assessment using intra-class correlation (ICC):intra-class coefficient=0.89 (0.95). CONCLUSIONS: We conclude that a pattern of zonal T1 variation does seem to exist that is unique for different sub-groups of FAI. The FA GRE approach to perform 3D T1 mapping has a promising role for further studies of standard MRI and dGEMRIC in the hip joint.

Conventional radiographs to assess femoroacetabular impingement

Femoroacetabular impingement (FAI) is a pathologic condition of the hip joint in young adults that, if untreated, leads to end-stage osteoarthritis. It is characterized by early pathologic contact between primary osseous prominences of the acetabular rim (so-called pincer FAI) and/or the femoral head-neck junction (cam FAI). Conventional radiographs are often considered normal because classic radiographic signs of osteoarthritis are not present initially. The physician should be aware of the radiographic features for both types of impingement to recognize subtle pathologies.

The effects of impingement and dysplasia on stress distributions in the hip joint during sitting and walking: a finite element analysis

Soft tissue damage has been observed in hip joints with pathological geometries. Our primary goal was to study the relationship between morphological variations of the bony components of the hip and resultant stresses within the soft tissues of the joint during routine daily activities. The secondary goal was to find the range of morphological parameters in which stresses are minimized. Computational models of normal and pathological joints were developed based on variations of morphological parameters of the femoral head (Alpha angle) and acetabulum (CE angle). The Alpha angle was varied between 40 degrees (normal joint) and 80 degrees (cam joint). The CE angle was varied between 0 degrees (dysplastic joint) and 40 degrees (pincer joint). Dynamic loads and motions for walking and standing to sitting were applied to all joint configurations. Contact pressures and stresses were calculated and crosscompared to evaluate the influence of morphology. The stresses in the soft tissues depended strongly on the head and acetabular geometry. For the dysplastic joint, walking produced high acetabular rim stresses. Conversely, for impinging joints, standing-to-sitting activities that involved extensive motion were critical, inducing excessive distortion and shearing of the tissue-bone interface. Zones with high von Mises stresses corresponded with clinically observed damage zones in the acetabular cartilage and labrum. Hip joint morphological parameters that minimized were 20 degrees

[Rehabilitation of a periodontally compromised dentition with implant-supported zirconia bridges. Case report]

Clinical aspects of reconstruction with fix prosthesis and dental implants in a patient with a history of periodontitis is shown. A successful stabilization and rehabilitation of the periodontally involved dentition can be achieved with tooth-worn crown and bridge reconstructions. From a functional and aesthetic point of view the result may not be satisfying due to mobility and overlength of the teeth and open approximal spaces. Today, dentist and patient have often to weigh if teeth shall be maintained or replaced by dental implants. Thereby, both must be aware of the fact that in complex cases long-term success and aesthetic outcome may be difficult to predict. An intense discussion with the patient on his expectations, invasive treatment, risks with regard to biologic and prosthetic aspects is mandatory and must be based on the best scientific evidence available. The present case report shows different considerations and describes a radical solution which meets the patient's needs and is based on modern CAD-CAM technology.

Die generative Herstellung von Dentalmodellen- eine Rapid Manufacturing Herausforderung

Heutzutage stehen zunehmend – z.B. durch den raschen Fortschritt bei den bildgebenden Verfahren – digitale Datensätze im Dentalbereich zur Verfügung. CAD/CAM-syteme gehören dabei in der Zahntechnik längst zum Stande der Technik. Für die Anwendung derartiger Systeme ist jedoch ein Gipsmodell nötig, welches zum Beginn der Prozesskette vom Zahntechniker mittels eines optischen Scanners digitalisiert wird. Die Weiterentwicklung intraoraler Scanner ermöglicht heutzutage außerdem die Digitalisierung ganzer Kiefer im Patientenmund durch den Zahnarzt. Insbesondere für z.B. die ästhetischen Restaurationen bildet hier das zahntechnische Modell nach wie vor die unersetzliche Arbeitsgrundlage für den Techniker. In der vorliegenden Arbeit wird dazu ein Rapid Manufacturing Verfahren zur Herstellung von Dentalmodellen auf Basis der Stereolithographie vorgestellt. Dabei wird auf die besonderen Anforderungen hinsichtlich Präzision, Robustheit und Wirtschaftlichkeit von generativen Fertigungsverfahren für dentale Applikationen eingegangen und eine neu entwickelte Baustrategie vorgestellt, mittels derer die o.g. Anforderungen erfüllt werden

Funktionales Konstruieren – Rapid Technologien für Architektur und Baukonstruktion

Nicht nur in der Medizintechnik, in der Luftfahrt und in der Automobilindustrie werden die generativen Verfahren zunehmend mehr als wichtige Produktionsverfahren angesehen. Auch die (Bau-) Industrie nimmt mehr und mehr die Möglichkeiten und Chancen wahr, welche diese Verfahren für andersartige Konstruktionen und Details eröffnen. Die Ergründung von Veränderungen und Auswirkungen dieser neuen Technologien auf den Entwurf und auf die Umsetzung von Architektur und Baukonstruktion ist Schwerpunkt der Forschungstätigkeiten von Dipl.-Ing. Holger Strauß an den Hochschulstandorten TU Delft, Niederlande und an der Hochschule Ostwestfalen-Lippe in Detmold. Das erste, umfangreiche Forschungsprojekt zu diesem Thema - „Influence of Additive Processes on the development of facade constructions“ - wurde 2008 in Kooperation mit der international agierenden Firma Kawneer-Alcoa im Forschungsschwerpunkt „ConstructionLab“ an der Detmolder Schule für Architektur und Innenarchitektur etabliert. Der Fokus der Bestrebungen liegt zunächst auf der Ergründung von Möglichkeiten für die generative Herstellung von Bauteilen als Ergänzung der Standardprodukte in Systemfassaden. Die Verwendung der Additiven Verfahren und Hightech CAD-CAM Anwendungen bedingt eine neue Art des Konstruierens. Nämlich nicht mehr das fertigungsgerechte, sondern das funktionsgerechte – das „Funktionale Konstruieren“. Neben der Bereicherung der Forschung und Lehre an den Hochschulen durch eine praxisnahe und zielorientierte Aufgabenstellung, fließen alle Ergebnisse in die Promotion von Holger Strauß an der Technischen Universität in Delft am Lehrstuhl Design of Construction bei Prof. Dr.-Ing. Ulrich Knaack ein.

Light curing through glass ceramics with a second- and a third-generation LED curing unit: effect of curing mode on the degree of conversion of dual-curing resin cements

Objectives The aim of this study was to measure the degree of conversion (DC) of five dual-curing resin cements after different curing modes with a second- and a third-generation light-emitting diode (LED) curing unit. Additionally, irradiance of both light curing units was measured at increasing distances and through discs of two glass ceramics for computer-aided design/manufacturing (CAD/CAM). Materials and methods Irradiance and spectra of the Elipar FreeLight 2 (Standard Mode (SM)) and of the VALO light curing unit (High Power Mode (HPM) and Xtra Power Mode (XPM)) were measured with a MARC radiometer. Irradiance was measured at increasing distances (control) and through discs (1.5 to 6 mm thickness) of IPS Empress CAD and IPS e.max CAD. DC of Panavia F2.0, RelyX Unicem 2 Automix, SpeedCEM, BisCem, and BeautiCem SA was measured with an attenuated total reflectance–Fourier transform infrared spectrometer when self-cured (negative control) or light cured in SM for 40 s, HPM for 32 s, or XPM for 18 s. Light curing was performed directly (positive control) or through discs of either 1.5- or 3-mm thickness of IPS Empress CAD or IPS e.max CAD. DC was analysed with Kruskal–Wallis tests followed by pairwise Wilcoxon rank sum tests (α = 0.05). Results Maximum irradiances were 1,545 mW/cm2 (SM), 2,179 mW/cm2 (HPM), and 4,156 mW/cm2 (XPM), and all irradiances decreased by >80 % through discs of 1.5 mm, ≥95 % through 3 mm, and up to >99 % through 6 mm. Generally, self-curing resulted in the lowest DC. For some cements, direct light curing did not result in higher DC compared to when light cured through ceramic discs. For other cements, light curing through ceramic discs of 3 mm generally reduced DC. Conclusions Light curing was favourable for dual-curing cements. Some cements were more susceptible to variations in curing mode than others. Clinical relevance When light curing a given cement, the higher irradiances of the third-generation LED curing unit resulted in similar DC compared to the second-generation one, though at shorter light curing times.